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Abstract:

The invention relates to the use of long chain polyunsaturated fatty
acids for the manufacture of a nutritional composition for feeding
infants of a mother who suffered from a metabolic disorder during
pregnancy and to a corresponding composition. Said composition comprises
a n-3 polyunsaturated fatty acid fraction containing at least 0.1 wt %
docosahexaenoic acid (DHA) based on total weight of the lipid, at least
0.01 wt % n-3 docosapentaenoic acid (DPAn-3) based on total weight of the
lipid, and at least 0.01 wt. % eicosapentaenoic acid (EPA) based on total
weight of the lipid, wherein the sum of DHA, DPAn-3 and EPA is below 1
wt. % of total lipid.

Claims:

1-12. (canceled)

13. A method for treating infants of a mother who suffered from diabetes
type I, diabetes type II, obesity or overweight during pregnancy, said
method comprising feeding a liquid nutritional composition to said
infant, wherein said liquid nutritional composition comprises: (a) a n-3
polyunsaturated fatty acid fraction containing at least 0.1 wt %
docosahexaenoic acid (DHA) based on total weight of the lipid; (b) at
least 0.01 wt % n-3 docosapentaenoic acid (DPAn-3) based on total weight
of the lipid; and (c) at least 0.01 wt. % eicosapentaenoic acid (EPA)
based on total weight of the lipid; and wherein the sum of DHA, DPAn-3
and EPA is below 1 wt. % of total lipid.

14. The method of claim 13, wherein said liquid nutritional composition
further comprises an n-6 polyunsaturated fatty acid fraction which
comprises: (a) between 0.05 and 0.4 wt. % gamma linoleic acid (GLA) based
on total weight of the lipid; (b) between 0.2 and 1 wt. % arachidonic
acid (AA) based on total weight of the lipid; and (c) between 10 and 15
wt. % linoleic acid (LA) based on total weight of the lipid.

15. The method of claim 13, wherein said liquid nutritional composition
further comprises between 1.5 and 3 wt.-% alpha linoleic acid (ALA) based
on total weight of the lipid.

16. The method of claim 14, wherein said liquid nutritional composition
further comprises between 1.5 and 3 wt.-% alpha linoleic acid (ALA) based
on total weight of the lipid.

17. The method of claim 16, wherein the weight ratio of LA/ALA is between
5 and 10.

18. The method of any one of claims 13-17, wherein: the weight ratio of
EPA/DHA is between 0.05 and 1; the weight ratio of (DPAn-3+EPA)/DHA is
between 0.25 and 1; the weight ratio of DPAn-3/EPA is between 0.25 and 5;
and the weight ratio of DHA/DPAn-3 is between 2 and 25.

Description:

FIELD OF THE INVENTION

[0001] The present invention relates to the use of a long chain
polyunsaturated fatty acid composition for feeding an infant of a mother
who suffered from a metabolic disorder during pregnancy and a nutritional
composition with polyunsaturated fatty acids suitable for such use.

BACKGROUND OF THE INVENTION

[0002] The polyunsaturated fatty acid status of infants is of continuing
interest in the art. Several functions have been attributed to different
fatty acids. For example, docosahexaenoic acid (DHA) is the primary
structural fatty acid component in both the gray matter of the brain and
the retina of the eye and thus is essential for brain and eye function.
Hence, DHA is of particular importance for the growing infant.

[0003] As a result of DHA deficiency, n-6 docosapentaenoic acid (DPA n-6)
is instead incorporated in the growing brain of the infant. This is
undesirable because it is difficult to reverse and may result in impaired
neurological development. Additional, insufficient DHA may lead to a
hindrance of healthy development.

[0004] DHA deficiency is of particular importance for infants of mothers
who suffered from a disease during pregnancy. Hence, particularly for
these infants, it is of crucial importance that the infant formula
provides an optimal fatty acid profile in the infant.

[0005] DE 4 327 310 describes a milk composition from cows containing
eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and n-3
docosapentaenoic acid (DPA-n3), which is useful for promoting growth,
intellectual function and sight function in children. The fat composition
is however unsuitable for feeding to an infant because the weight ratio
linoleic acid/alpha-linolenic acid (LA/ALA) is not optimal.

[0006] WO 01/78530 describes a nutritional composition containing
specified amounts of docosahexaenoic acid (DHA) and arachidonic acid (AA)
as well as their precursor essential fatty acids ALA and LA, for
providing nutrition and for enhancing neurological development of preterm
infants.

[0007] WO 2004/052115 describes glyceride compositions, methods of making
the glyceride compositions, and nutritional formulations containing the
glyceride compositions. The glyceride compositions contain predominantly
monoglycerides and diglycerides carrying one or more long chain
polyunsaturated fatty acids. Also disclosed are methods of using the
glyceride compositions and nutritional formulations.

[0009] The object of the present invention is to provide a nutritional
composition with polyunsaturated fatty acids suitable for feeding an
infant of a mother who suffered from a metabolic disorder during
pregnancy.

SUMMARY OF THE INVENTION

[0010] The present inventors believe that not only DHA and AA need to be
abundantly present in infant formula for optimal brain development, but
also the precursors of these fatty acids are essential because an
important part of the DHA and AA are locally synthesized in the brains
from its precursors. Hence, the present inventors believe that addition
of DHA and/or AA alone to the standard infant formulas is insufficient to
provide optimal DHA incorporation in the various neurological tissues.
Hence the present composition also contains, besides DHA and AA,
significant amounts of precursors of DHA and AA.

[0011] For an optimal de novo synthesis, the present composition contains
the precursors of DHA, including at least alpha-linolenic acid (ALA),
eicosapentaenoic acid (EPA) and n-3 docosapentaenoic acid (DPA-n3).
However, EPA cannot be included in the composition in to high amounts, as
EPA inhibits the metabolic conversion of linolenic acid (LA) to AA,
another important fatty acid. The relatively low EPA amounts are
compensated for by relatively high quantities of docosapentaenoic acid
(DPAn-3) in the present composition. Both precursors are essential,
because they are believed to provide the precursors, which stimulate the
local DHA synthesis.

[0012] Hence, in an optimal configuration,

[0013] the weight EPA/DHA ratio in the present composition is between 0.05
and 1, which is similar or a little below the ratio of the average human
milk;

[0014] the weight ratio long chain DHA precursor [DPAn-3+EPA] per DHA is
preferably between 0.25 and 1 in order to provide sufficient DHA
precursor; and

[0015] the weight ratio DPA-n3/EPA of the present composition is between
0.25 and 5. Human milk generally has a weight ratio DPA-n3/EPA above
about 1.

[0016] High DPAn-3 oils, which can be suitably used, include marine oils
such as seal oil and DPAn-3-enriched fish oils. The present composition
has a weight ratio DHA/DPAn-3 of between 2 and 25, slightly above the
average content weight ratio DHA/DPA-n3 in human milk, but a major
improvement over the available infant formula containing no or only trace
amounts of DPA-n3.

[0017] In order to further improve the composition, ALA is added in
significant amounts to further reduce insufficiency of DHA. The ratio
ALA/DHA in the present composition is preferably between 5 and 25.

[0018] Furthermore, it is of great importance that arachidonic acid (AA)
is included in the present composition, particularly in those
compositions containing long chain precursors of docosahexaenoic acid. AA
is an omega-6 fatty acid derived from linoleic acid and is found
primarily in food sources such as meat, eggs and milk. AA contains twenty
carbon atoms and four double bonds (20:4n-6) and is the principal omega-6
fatty acid found in the brain. Besides AA it is also of primary
importance that the lipid contains significant amounts of AA precursor,
i.e. gamma linolenic acid (GLA) and linoleic acid (LA). These fatty acids
provide the precursor for local synthesis of AA. Because the present
composition has a high GLA content, i.e. preferably between 0.05 and 0.4
wt. % GLA based on total weight of the lipid, the present composition has
a low linoleic acid content, i.e. between 10 and 15 wt. % LA based on
total weight of the lipid.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The present invention provides a nutritional composition wherein
the carbohydrate provides 40 to 75% of the total calories, the lipid
provides 20 to 50% of the total calories and the protein provides 5 to
12.5% of the total calories, wherein the lipid contains at least one
vegetable lipid source and a n-3 docosapentaenoic acid (DPAn-3)
containing lipid source, said lipid contains an n-3 polyunsaturated fatty
acid fraction and an n-6 polyunsaturated fatty acid fraction, wherein

[0020] the n-3 polyunsaturated fatty acid fraction contains

[0021] at least 0.1 wt % docosahexaenoic acid (DHA) based on total weight
of the lipid; at least 0.01 wt % DPAn-3 based on total weight of the
lipid; at least 0.01 wt. % eicosapentaenoic acid (EPA) based on total
weight of the lipid; wherein the sum DHA, DPAn-3 and EPA is below 1 wt. %
of total lipid; and between 1.9 and 3 wt. % alpha linoleic acid (ALA)
based on total weight of the lipid; and the weight ratio: EPA/DHA ratio
between 0.05 and 1; (DPAn-3+EPA)/DHA 0.25 and 1; DPAn-3/EPA 0.25 and 5;
DHA/DPAn-3 between 2 and 25; ALA/DHA between 5 and 25,

[0022] the n-6 polyunsaturated fatty acid fraction contains

[0023] between 0.2 and 1 wt. % arachidonic acid (AA) based on total weight
of the lipid; and between 10 and 15 wt. % linoleic acid (LA) based on
total weight of the lipid; and

[0024] the weight ratio LA/ALA is between 5 and 10.

[0025] The present composition, which can be considered as a nutrition
containing a lipid blend, can suitably be used for feeding healthy
infants and is particularly suitable for feeding an infant of a mother
who suffered from a metabolic disorder during pregnancy. The n-3
polyunsaturated fatty acid fraction as described above provides
significant benefits for these infants. Optimally, the composition as
described above contains both the n-3 polyunsaturated fatty acid fraction
and the n-6 polyunsaturated fatty acid fraction as described herein.

[0026] In a further aspect the present invention provides the use of long
chain polyunsaturated fatty acids for the manufacture of a nutritional
composition, which is preferably a liquid composition, for feeding
infants of a mother who suffered from a metabolic disorder during
pregnancy, said composition comprising a n-3 polyunsaturated fatty acid
fraction containing at least 0.1 wt % A) docosahexaenoic acid (DHA) based
on total weight of the lipid; and at least 0.01 wt % n-3 docosapentaenoic
acid (DPA-n3) based on total weight of the lipid; and at least 0.01 wt. %
eicosapentaenoic acid (EPA, n3) based on total weight of the lipid; and
wherein the sum DHA, DPA-n3 and EPA is below 1 wt. % of total lipid. Said
nutritional composition can have any form desired and/or suitable for
feeding purposes and is preferably in the form of a liquid.

[0027] The present composition is particularly suitable for infants of
mothers who suffered from one or more of diabetes type I, diabetes type
II, overweight and obesity during pregnancy. These metabolic disorders
are a particular cause of reduced DHA and/or DHA precursor transmittal of
the mother to the infant and may result in increased DPAn-6 incorporation
into the brain membranes.

[0030] The present composition contains a n-3 polyunsaturated fatty acid
fraction comprising at least 0.1 wt %, preferably between 0.10 and 1 wt.
%, more preferably between 0.15 and 0.5 wt. % DHA based on total weight
of the lipid. The present composition contains at least 0.01 wt %,
preferably between 0.015 and 0.5 wt % DPAn-3 based on total weight of the
lipid. The EPA content is at least 0.01 wt. %, preferably between 0.03
and 0.5 wt. %, even more preferably between 0.04 and 0.1 wt. % based on
total weight of the lipid.

[0032] The present composition has a weight ratio EPA/DHA between 0.05 and
1, preferably between 0.1 and 0.5, more preferably between 0.2 and 0.5.
The weight ratio DHA/DPAn-3 of the present composition is between 2 and
25, preferably between 5 and 15. The weight ratio (DPAn-3+EPA)/DHA of the
present composition is between 0.25 and 1. More optimally, the weight
ratio (precursors of DHA/DHA), i.e. (DPAn-3+EPA)/DHA, is between 0.3 and
0.5. In mothers milk, the weight ratio DPAn-3/EPA is generally greater
than 1. The present composition preferably has a weight ratio DPAn-3/EPA
between 0.25 and 5, more preferably between 0.3 and 3. Particular
DPAn-3-enriched fish oils, selected seal oils and biotechnologically
produced high DPAn-3 oils may suitably be used for making the composition
according to the present invention.

[0033] The present composition contains between 1.9 and 3 wt. %,
preferably between 2 and 2.5 wt. % ALA based on total weight of the
lipid. The wt. % ALA is slightly increased compared to mother's milk.
Mothers milk generally contains between about 0.5 and 1.6 wt. % ALA based
on total weight of the lipid. However, mothers milk generally contains an
increased weight percentage of long chain precursors of DHA, e.g. DPAn3
and EPA. Hence, the weight ratio ALA/DMA is higher in the present
composition compared to mother's milk, i.e. between 5 and 25 in the
present composition, versus about 2 in mother's milk. Preferably the
ratio ALA/DHA in the present composition is between 7.5 and 15.

[0036] The present composition contains between 0.2 and 1 wt. %,
preferably between 0.25 and 0.75 wt. % AA based on total weight of the
lipid. AA cannot be incorporated into the composition in to high amounts
because of its pro-inflammatory effects. Hence, as a precursor of AA, the
present composition preferably contains between 0.05 and 1 wt. %,
preferably between 0.1 and 0.4 wt. %, more preferably between 0.15 and
0.3 wt. % GLA based on total weight of the lipid. The high content of GLA
is included in the present composition to at least partially compensate
for the reduced amount of DGLA in the present composition compared to
human milk. As still the cumulative amount of precursor is relatively
low, the present composition contains a high amount of LA, i.e. between
10 and 15 wt. %, preferably between 11 and 14 wt. % LA based on total
weight of the lipid, which is slightly elevated compared to the average
content of LA in human milk, which is about 9 wt. % (Luukainen at al, Eur
J Pediatr (1995) 154: 316-319). The incorporation of the present amounts
of GLA and the optimal n-3 polyunsaturated fatty acid fraction does
however not require excessive amounts of LA to be included in the present
composition, i.e. above 15 wt. % LA based on total lipid.

[0037] The weight ratio LA/ALA in the present composition is between 5 and
10.

[0038] Infant nutrition:

[0039] The present invention relates to nutritional formula suitable for
feeding to an infant, i.e. nutritional compositions wherein the
carbohydrate provides 40 to 75%, the lipid provides 20 to 50% and the
protein provides 5 to 12.5% of the total calories. Preferably the protein
provides 7.5 to 12.5% of the total calories.

[0040] The present composition contains at least one vegetable lipid
source and a DPAn-3 containing lipid source. More preferably, the present
composition contains at least one lipid source selected from the group
consisting of evening primrose oil, borage oil and blackcurrant seed oil;
at least one lipid source selected from the group consisting of canola
oil, sunflower oil, coconut oil, palm oil and soybean oil; and at least
one DPAn-3 containing lipid source, In a further preferred embodiment,
the present composition also contains a fungal oil. Preferably the DPAn-3
containing lipid source contains at least 1 wt. %, even more preferably
at least 2 wt. % DPA n-3 based on fatty acids of the DPAn-3 containing
lipid source. For easy manufacturing, the DPAn-3 containing lipid source
contains at least 15 wt. %, more preferably at least 20 wt. % DHA, even
more preferably at least 25 wt. % DHA based on fatty acids of the DPAn-3
containing lipid source.

[0041] In a further aspect the present invention provides a method for
treating infants of a mother who suffered from a metabolic disorder
during pregnancy by administering the present composition.

[0042] For the preparation of the present composition, a blend of animal
and vegetable lipid sources is used. Because the fatty acid constitution
of lipid sources can vary significantly (even if obtained from the same
plant or animal source), it is best to first analyze the lipid source to
be used and than calculate the amounts of individual oils that are needed
to achieve the present composition and admix the lipid sources.
Alternatively, the skilled person can find the appropriated lipid sources
in proper handbooks. The lipid source used are preferably of non-human
origin. The fatty acids as described in the present invention may be
provided as free fatty acids, in triglyceride form, in phospholipid form,
or as a mixture of one of more of the above.

[0043] The carbohydrate of the present composition is preferably provided
mainly by lactose, because it is most suitable for feeding the infant.
Hence, the digestible carbohydrate fraction (carbohydrate) preferably
contains at least 50 wt. %, more preferably at least 90 wt. % lactose
based on total weight of the carbohydrate fraction.

[0044] Sleep is also of utmost importance for proper intellectual
development of the infant. Hence, the infant preferably has reduced
intestinal discomfort. Water-soluble indigestible fibers contribute a
reduced occurrence of intestinal discomfort such as bloating. Hence, the
present composition preferably also contains between 0.2 and 5 grams
water-soluble indigestible fiber per 100 kcal of the present composition,
more preferably between 0.5 and 1.5 gram per 100 kcal. Preferably the
present composition contains at least one water-soluble indigestible
fiber selected from the group consisting of galactooligosaccharide,
fructooligosaccharide and inulin.

[0045] Optimal brain development is of particular importance for the baby
the first few months of life. Hence, the present invention particularly
relates to nutritional formulas, which are optimally suitable for feeding
during the first few months of life. A caloric content of between 0.600
and 0.800 kcal per ml is believed to reduce intestinal discomfort in
these young infants and thereby stimulate the uptake of fatty acids.
Hence, the present composition preferably contains between 0.600-0.800
kcal/ml, more preferably 0.650-0.680 kcal/ml.

[0046] As the infants of mothers who suffered from a disease during
pregnancy may have sometimes have to catch-up on neurological tissue
development, the present invention preferably comprises nucleotides. The
present composition preferably also comprises between 2 and 25 mg
nucleotides and/or between 2 and 25 mg nucleosides per 100 kcal, more
preferably between 3 and 10 mg nucleotides per 100 kcal. The present
composition preferably contains at least 2 nucleotides selected from the
group consisting of cytidine-5-monophosphate, uridine-5-monophosphate,
adenosine-5-monophosphate, guanosine-5-monophosphate and
inosine-5-monophosphate. The nucleotides and/or nucleosides further
stimulate the immune system, acting synergistically with the other
ingredients of the present composition.

EXAMPLES

Example 1: Infant Formula

[0047] A liquid infant nutrition, prepared by admixing 13.9 g powder with
water to yield 100 ml final product, said liquid product comprising per
100 ml:

[0048] Energy: 66 kcal

[0049] Protein: 8 en %

[0050] Digestible Carbohydrates: 44 en % (containing 7.3 g lactose)

[0051] Lipid: 48 en % (containing, based on total weight of the lipid 0.2
wt. %